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VLA-4 inhibitory drug

a technology of inhibitors and vla4 is applied in the field of vla4 inhibitors, which can solve the problems of short retention time in blood and poor oral absorption of most such compounds, and achieve excellent effects and high oral absorption

Inactive Publication Date: 2012-03-06
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034]The VLA-4 inhibitory drug of the present invention has high oral absorbability, and also exerts excellent effects on the predominant pharmacological and pathological in vivo model when administered orally. Thus the inhibitory drug of the invention makes it possible to prevent and / or treat various diseases caused by the migration and adhesion of leukocytes mediated by VLA-4, such as inflammatory response and autoimmune diseases.

Problems solved by technology

Although an orally administrable agents is regarded as preferable in teaching inflammatory diseases, it is also known that most of such compounds have poor oral absorbability and tend to suffer a short retention time in blood.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

4-[(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]benzoic acid ethyl ester

[0401]

[0402]To a methanol solution (300 mL) of 4-[1-(benzyloxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]benzoic acid ethyl ester (25.5 g, 63.8 mmol), 106 palladium hydroxide / carbon (5.1 g) was added, and the mixture was stirred for 4 hours under a hydrogen stream at normal pressure. The reaction mixture was filtered to eliminate the catalyst, and then the filtrate was concentrated under reduced pressure and dried, to obtain the title compound (17.9 g, 100%) as a solid.

[0403]NMR (CDCl3) δ: 1.38 (3H, t, J=7.1 Hz), 1.77-2.03 (total 3H, series of m, including 1H, broad s, at δ 1.91), 2.96-3.00 (1H, m), 3.11-3.15 (1H, m), 3.81-3.99 (3H, m), 4.34 (2H, q, J=7.1 Hz), 4.49-4.51 (1H, m), 6.91 (2H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz).

4-[1-(Tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarbox...

example 2

Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester

[0443]NMR (CDCl3) δ: 1.19-1.51 (9H, m), 1.87-2.33 (6H, m), 2.80-3.01 (3H, m), 3.16-3.25 (1H, m), 3.26 (0H, s), 3.26 (3H, s), 3.43-3.83 (7H, m), 3.87 (3H, s), 3.92-4.25 (4H, m), 7.32-7.44 (4H, m), 7.78-7.81 (1H, m), 8.10-8.17 (1H, m), 8.23 (1H, s), 8.77 (1H, dd, J=6.7, 1.1 Hz).

[0444]MS (ESI) m / z: 699 (M++1), 701 (M++3)

Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

[0445]

[0446]NMR (CDCl3) δ: 1.15-1.57 (4H, m), 1.92-2.42 (6H, m), 3.28-3.96 (18H, m), 4.09-4.43 (2H, m), 7.29-7.45 (4H, m), 7.81 (1H, s), 8.12 (1H, t, J=4.5 Hz), 8.24 (1H, d, J=4...

example 3

Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester

[0451]NMR (CDCl3) δ: 1.13-1.55 (9H, m), 1.88-2.34 (6H, m), 2.80-3.01 and 3.27 (total 3H, each s, amide isomers), 3.44-3.85 (7H, m), 3.97-4.21 (4H, m), 7.39-7.55 (3H, m), 7.92 (1H, d, J=8.1 Hz), 8.10 (1H, d, J=5.9 Hz), 8.34 (1H, d, J=7.4 Hz), 8.39-8.51 (2H, m).

[0452]MS (ESI) m / z: 685 (M++1), 687 (M++3)

Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

[0453]

[0454]NMR (CDCl3) δ: 1.37-1.37 (4H, m), 1.87-2.35 (7H, m), 2.99-3.30 and 7.91 (total 1H, each d, J=8.3 and 8.1 Hz, respectively, amide isomers), 8.09 (1H, d, J=4.4 Hz), 8.34 (1...

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Abstract

There is provided a VLA-4 inhibitory drug having good oral absorbability and exhibiting sufficient anti-inflammatory effects when administered orally.A compound represented by the following formula (I):wherein R1 represents a hydrogen atom or a C1-8 alkyl group; R2 represents a hydrogen atom, a halogen atom, a C1-8 alkoxy group, or a benzyloxy group which may be substituted; Q represents a monocyclic or bicyclic nitrogen-containing heterocyclic group which may be substituted, and has a nitrogen atom as the bonding site; Y represents an oxygen atom or CH2; W represents a bicyclic aromatic hydrocarbon ring group which may be substituted, or a bicyclic aromatic heterocyclic group which may be substituted; R3a, R3b and R3c each independently represent a hydrogen atom, a halogen atom, a C1-8 alkoxy group or a C1-8 alkyl group; and A1 represents a nitrogen atom or C—R3d (wherein R3d represents a hydrogen atom, a halogen atom, a C1-8 alkoxy group or a C1-8 alkyl group),or a salt thereof, or a VLA-4 inhibitory drug comprising the compound or the salt as an active ingredient.

Description

TECHNICAL FIELD[0001]The present invention relates to a VLA-4 inhibitory drug that has a novel cyclohexanecarboxylic acid skeleton and is orally administrable.BACKGROUND ART[0002]Leukocyte is well known to play a critical role in inflammatory reactions that could be caused by microbial intrusion, the damaged tissue or the like. It is also known that leukocytes usually circulate in the blood vessel and, once the tissue is inflamed, leukocytes are infiltrated into the inflamed tissue by passing through the blood vessel wall adjacent to the such a tissue. This infiltration is found to be associated with the integrins expressed on the surface of a leukocyte cell.[0003]An integrin is composed of a heterodimer of glycoprotein in which two noncovalently associated subunits (i.e., α-subunit and β-subunit) coalesce with each other. So far, at least 16 species are known to be included in the family of α-subunit, while at least 9 species are known to be included in the family of β-subunit, and...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/553C07D243/08
CPCC07D401/12C07D401/14C07D403/12C07D403/14C07D405/12C07D405/14C07D409/12C07D409/14C07D413/14C07D417/14C07D487/08C07D491/048C07D491/056C07D491/08C07D495/04A61P1/00A61P1/04A61P1/16A61P11/02A61P11/06A61P11/08A61P13/12A61P17/06A61P19/02A61P25/00A61P27/02A61P27/16A61P29/00A61P3/10A61P35/00A61P35/02A61P35/04A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P9/10
Inventor MACHINAGA, NOBUOIIMURA, SHINYONEDA, YOSHIYUKICHIBA, JUNMURO, FUMIHITOHOH, HIDEKONAKAYAMA, ATSUSHI
Owner DAIICHI SANKYO CO LTD
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